Effects of Retinoic Acid Signaling on Retinal Ganglion Cell Survival and Regeneration. Recovery of vision after optic nerve injury requires retinal ganglion cell (RGC) survival, axonal regrowth past the area of the lesion and reformation of appropriate synaptic targets. The adult mammalian visual system regenerates poorly, and past therapeutic efforts have enabled regrowth of only a small number of retinal axons. Frog RGCs, on the other hand, suffer an approximately 50% cell loss after injury, but regeneration and reconnection to target areas still occur because of the lack of inhibitory glial molecules and physical obstructions. This makes them a good model to explore which molecules influence RGC regeneration. Understanding what occurs after RGC injury is of great medical importance, because it results in blindness after optic nerve injury, and also in conditions such as glaucoma, diabetes and optic ischemia. The focus of the proposed work is to understand how the activity of retinoic acid (RA) signaling, known to exert effects on neurite outgrowth and homeostatic synaptic plasticity in the brain, affects the processes leading to recovery of vision after axotomy in the adult visual system. The aims of this proposal are to (1) determine the role of RA and the intracellular signaling pathways it activates in promoting RGC survival after injury, (2) determine the role of RA promoting regeneration of RGC axons, and (3) investigate the effects of RA on the reformation of synaptic connections in the retinorecipient layer of the optic tectum. The first aim will be accomplished by quantification of numbers of surviving RGCs, and Western blot analysis of regenerating retinal tissue. The second aim will be addressed by measuring the number of viable retinal axons crossing the lesion area, changes in the speed of regeneration, and changes in the abundance of GAP43 (regeneration marker) and NAV-2 (responsive gene in RA-mediated neurite outgrowth) in non-treated optic nerves and nerves from animals treated with RA signaling agonists and antagonists. The effect of RA signaling on the activation of relevant intracellular signaling pathways in regenerating RGCs will also be studied. The third aim will be carried out by quantifying anterogradely labeled retinal axons, the number of functional synaptic inputs, and the distribution of synaptic proteins in the retinorecipient layer f optic tectum after altering retinoic acid signaling and axotomy. Understanding the role of RA signaling in the response of retinal ganglion cells to nerve injury is important for the design of potential new therapeutic strategies.